It takes two (IL-2) to Tango!!!!!

Immune responses involve multiple cell-cell interactions within lymphoid tissues, thetrafficking of activated cells to sites of effector function, and the migration of such effector cells within peripheral tissues. To gain a more detailed appreciation of the dynamics of such cell behavior and the relationship between cell dynamics and function, I have put together a series of events that take place during the activation phase of the immune response.We know based on research that once the CD4+ T cell is activated, within two hours the IL-2 expression and IL-2 receptor are unregulated. IL-2 is secreted 45 minutes into this activation phase.

Experimental work has shown that IL-2 signaling in the first 10 hours is critical for the proliferation decision of T cells in culture. The spacial resolution of the Tregs and the T helper cells during this phase plays a mojor part in the immune response.Secreted IL-2 is competed for by the Tregs and the activated CD4+ and CD8+ T-cells. If the Tregs are in close proximity of the T effector cells, the Tregs will create an IL-2 sink in the microenvironment. This will cause the proliferation and survival of the Tregs. This IL-2 sink is where all the IL-2 that is secreted by the T helper cells is adsorbed by the IL-2 receptors on the Tregs cell. Tregs don’t have the capability to produce IL-2.

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The model proposed by Dr. Dorothea Busse and colleages predicts that the IL-2 secretion rate must exceed a threshold value Theta (θ) to switch IL-2Rα expression to the activated state and permit extensive autocrine IL-2 signaling.

As you can see in the above diagram, you don’t need high concentration of IL-2, you need spacial distance from one cell to the other. That can be achieved by Anti-CTLA-4 Blockage. By blocking the CTLA-4 receptors,

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IL-2 is mainly captured by the Treg cell, whereas autocrine reuptake by the T helper cells predominates when the cells are further apart. So we want to introduce IL-2 before the tumor recruites the Tregs to the Tumor Microenviroment and or when the Treg population is in the contration phase of the CD4+ T-cell cycle.

Cellular signal response is potentially controlled by ratio between ligand (IL-2)number and surface receptor (IL-2R) number per cell. Sigmoid signal response is a general principle in different receptor trafficking networks.

Suboptimal amounts of IL-2 during priming promoted apoptosis, little proliferation and cell cycling, yet the CD8+ effectors generated produced high levels of cytokines and proliferated autonomously. This is the reason why it takes a while for the Tumors to begin to shrink because of little proliferation.

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Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectors generated under these conditions possessed optimal Effector functions.

So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cell subset?

1. Anti-CTLA-4 Blockage

2. Local IL-21 Promotes the Therapeutic Activity of Effector T cells by Decreasing Regulatory T Cells Within the Tumor Microenvironment

3. Anti-PD-1 Blockage

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